COSA:NETs guidelines/Cytotoxic chemotherapy and other systemic treatments

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Cytotoxic chemotherapy and other systemic treatments


Chemotherapy traditionally has had a limited role in the treatment of neuroendocrine tumours (NETs). However, some newer, targeted agents in particular, have shown a significant activity, which has broadened systemic therapeutic options for this disease.

Chemotherapy is mainly used in patients with progressive and metastatic pancreatic NETs after failure of other treatment modalities such as somatostatin analogues (SSAs) e.g. octreotide LAR. To date there is no evidence to support its use in adjuvant settings (after complete resection of the disease).

Tumour grade (determined by histological appearance, Ki-67 and mitotic index) may be useful for selecting systemic treatments. For example, chemotherapy may be more beneficial in high grade or poorly differentiated tumours whereas SSAs or targeted therapies may be preferable as early treatment for well differentiated disease.

Patients progressive on standard treatment should be offered participation in clinical trials.

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High grade tumours

High grade tumours are poorly differentiated with high proliferative/mitotic indices [>20 mitoses/10 HPF; Ki-67 index >20%]. They are usually metastatic at presentation and chemotherapy may be the only treatment option. High grade tumours are often managed similarly to small cell lung cancer.

In spite of lack of evidence, patients with resected high grade tumours and without evidence of residual disease are often offered ‘adjuvant’ chemotherapy. Consideration should also be given to radiotherapy in close or positive surgical margins. Extrapolating the data from the treatment of limited stage small cell lung carcinoma concurrent chemo and radiotherapy may be considered.

Combination of cisplatin or carboplatin with etoposide is commonly used with likelihood of tumour response 42–65%, duration of response 8–9 months, and median survival 15–19 months.[1][2]

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Low grade tumours

Heterogeneity of tumours of so called low grade potential is widely recognised. In spite of their well differentiated appearance on histology they can sometimes have an aggressive clinical course. Their behaviour may not only be variable between patients but also in an individual patient during the course of the disease. The decision to initiate systemic treatment should depend on factors such as the rate of disease progression and burden of disease related symptoms, whereas factors such as site of origin (pancreatic versus non-pancreatic), appearance on functional imaging, treatment history and treatment availability should be considered when choosing between treatments.

Metastatic tumors with low mitotic/proliferative indices [<2 mitoses/10 HPF; Ki-67 index <3%] can be slow growing and asymptomatic, and may not require systemic treatment for some time. Moderately differentiated (low grade malignant) tumors with intermediate mitotic/proliferative indices [2–20 mitoses/10 HPF; Ki-67 index 3–20%] have more uncertain behaviour requiring closer observation and sometimes earlier start of systemic treatment. Functional imaging (octreoscan and/or FDG PET) may help in choosing the type of systemic treatment. Intermediate grade NETs with octreotide non-avid but FDG PET positive lesions may require more aggressive chemotherapy regimens traditionally used in high grade NETs.

Somatostatin analogues may be considered as earlier-line systemic therapy in metastatic octreotide-avid with existing data suggesting anti-proliferative action in both midgut and pancreatic NETs of lower proliferative index (Ki67<10%).[3][4]

Efficacy of targeted agents such as sunitinib (reimbursed by the Australian Pharmaceutical Benefits Scheme, but not by Pharmac in New Zealand) and everolimus have also been shown in randomised trials in pancreatic NETs, and in these tumours may be considered prior to chemotherapy. Although data on optimal sequencing is not yet available the results from the aforementioned randomised trials appears more compelling than those of earlier studies of cytotoxic regimens, and some targeted agents may be better tolerated than some cytotoxic regimens.

Cytotoxic chemotherapy should still be considered after failure of these newer agents, or when they are not available. NETs of pancreatic origin are often more responsive to chemotherapy than non-pancreatic NETs. Streptozocin based regimens have been traditionally used in the majority of patients with pancreatic NETs. A randomised phase III study by Moertel et al in 1992 showed advantage for streptozocin and doxorubicin over streptozocin and 5-FU doublet with impressive response rate (69% vs 45%), response duration (20 vs 6.9 months) and median survival (26 vs 18 months).[5] Although further studies did not confirm the initial results (response rates 36-55%), streptozocin in combination with 5-FU and/or doxorubicin has been the standard of care for years.[6][7][8][9] Similar chemotherapy regimens in non-pancreatic NETs have shown less impressive results.[10][11][12]

More recently several newer chemotherapy regimens (dacarbazine, temozolomide and thalidomide or capecitabine) have shown promising activity. Similar to streptozocin based regimens they seem more effective in pancreatic than non-pancreatic NETs (dacarbazine 33% and 16%, temozolomide alone 14% and temozolomide with thalidomide 45% and 25%, respectively).[13][14][15] Similar to the treatment of glioblastomas, temozolomide is much more active in tumours lacking DNA repair enzyme MGMT with 51% response rates in pancreatic NETs.[16] The addition of capecitabine (an oral 5-FU prodrug) to temozolomide has shown promising activity in previously untreated pancreatic NETs in retrospective analyses[17][18] and deserves prospective validation.

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Interferon alpha

Due to its significant potential for side effects (myelosuppression, fatigue, depression, thyroid dysfunction, autoimmune syndromes) interferon alpha is rarely used as a front line treatment for NETs. When used as a single agent it achieves modest response rates (<10% RR, <25% SD) and it is inferior to SSAs in controlling tumour-related symptoms.[3] However, in its usual dose (3-9 mega units / 3-5 times per week) it may have a role in control of hypersecretion symptoms in combination with SSAs when they are not sufficiently controlled with SSAs.

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Monitoring of treatment response

Urine 5-HIAA

Urine 5-HIAA is most useful for monitoring serotonin secreting tumours (midgut NETs). It is elevated in >70% of patients. Higher levels can be expected in functioning and more advanced tumours. Malabsorption syndromes and tryptophan reach food can affect its level in urine.

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Serum Chromogranin A

Serum Chromogranin A (CgA) is a more sensitive marker than 5-HIAA in detection and monitoring of both functioning and non-functioning NETs (87% vs 73%). Again the levels are higher with more advanced tumours. Proton pump inhibitors can elevate serum CgA and should be withheld before the test.

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CT and Octreoscan have been traditionally used for staging and monitoring of treatment effects in NETs. Wherever possible triphasic CT should be used since it is more accurate in defining liver lesions. It is less clear when Octreoscan should be used. If it is available it should be used at diagnosis and when PRRT treatment is considered. FDG PET avidity is more likely in high grade tumours and may predict responsiveness to platinum/etoposide chemotherapy. Emerging evidence suggests that galium PET/CT may become the imaging method of choice in the future.

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Targeted therapies

NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Agents targeting the VEGF axis (e.g. sunitinib) and its downstream serine/threonine kinase mammalian target of rapamycin (mTOR) (e.g. everolimus) have shown a significant activity in recently published reports of randomised studies.

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VEGF / VEGFR inhibitors

Several VEGF and VEGFR tyrosine kinase inhibitors have been been studied mostly in pancreatic NETs. Significant reduction of tumour blood flow and improvement of PFS at week 18 (95% vs 68%; p=0.02) was noted with bevacizumab (monoclonal anti-VEGF Ab) when compared to pegylated interferon alpha.[19] When combined with temozolomide, bevacizumab showed impressive disease control rate (PR+SD) in both pancreatic and non-pancreatic NETs (94% and 92%, respectively). As expected there were more partial responses observed in pancreatic NETs (24% vs 0).[20] An impressive, although unconfirmed, PR rate (60%) was reported in a small number of patients with progressive NETs with combination of bevacizumab and FOLFOX. However, the patients with high grade tumours were also included in analysis.[21]

Sunitinib, a multikinase inhibitor (VEGFR, PDGFR, RET, c-Kit), achieved overall objective response rate of 16.7% in pancreatic and 2.4% in non-pancreatic NETs in an early study. In that study, median time to progression however, was longer in non-pancreatic then pancreatic NETs (10.2 and 7.7 months respectively), although one year survival rates were similar for both cohorts.[22] A recently published report of randomised trial of sunitinib versus placebo which enrolled patients with progressing advanced pancreatic neuroendocrine tumours has shown a significant improvement in progression free (11.4 vs 5.5 months, hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; p<0.001).[23] With longer term follow up, the overall survival improvement which was initially observed is no longer statistically significant, although a trend towards survival benefit is still suggested.[24]

Sunitinib is funded in Australia (but not in New Zealand) for the treatment of metastatic or unresectable well-differentiated malignant pancreatic neuroendocrine tumours in patients who are symptomatic despite SSA therapy or have documented disease progression.

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mTOR inhibitors

Evidence of mTOR involvement in pathogenesis of NETs is suggested by association of germline mutations in the mTOR pathway with NETs. Both of the currently available mTOR inhibitors, temserolimus and everolimus (RAD001) have been studied in patients with NETs.

Temserolimus has shown a modest objective response rate of 5.6% in a phase II study but higher baseline levels of phosphorylated mTOR (p=0.01) predicted for a better response. An increase in pAKT and decrease in phosphorylated mTOR after the treatment correlated well with increased time to progression.[25]

Everolimus showed a promising ORR (20%) and median PFS (60 weeks) in initial phase II study. [26] In a follow-on international phase II study (RADIANT-1) patients with advanced pancreatic NETs progressing after chemotherapy, were divided into two strata, everolimus alone (n=115) or everolimus plus octreotide (n=45) on the basis of whether the patients were receiving octreotide at study entry. The median PFS for patients receiving everolimus or everolimus and octreotide were 9.7 and 16.7 months, respectively. An early biomarker response (30% decrease or normalisation of CgA or NSE at week 4) correlated with superior PFS.[27] Everolimus (RAD001) has been shown to significantly improve progression free survival in metastatic pancreatic neuroendocrine tumours in a randomised phase III trial (RADIANT-3) compared to placebo (11 versus 4.6 months, hazard ratio for disease progression and death, 0.35; 95% CI 0.27 to 0.45; p<0.001), although no overall survival improvement was observed.[28] Crossover to everolimus in the placebo arm was allowed in the study, which does make overall survival difficult to interpret. Benefit is also suggested in a similar randomized study in patients with non-pancreatic neuroendocrine tumours and a history of the carcinoid syndrome, in which patients were treated with Sandostatin LAR with or without everolimus.[29] Although this study did not meet its primary end point of an improvement in central review evaluated progression-free survival (hazard ratio 0.77, but p=0.026, above pre-set cut off of 0.0246), there was still a clinically meaningful 5.1 month progression-free survival difference between arms, and progression free-survival by investigator review was significantly improved; interpretation of the overall survival results are also complicated by crossover.”

In metastatic well and intermediate differentiation pancreatic neuroendocrine tumours, the clear improvement in outcomes observed with the use of agents such as sunitinib and everolimus may make these agents preferable to chemotherapy earlier in the course of managing these patients.

Sunitinib and everolimus are not currently funded in New Zealand for the treatment of NETs and therefore are not available to the patients in the public system.

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  1. Moertel CG, Kvols LK, O'Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991 Jul 15;68(2):227-32 Available from:
  2. Mitry E, Baudin E, Ducreux M, Sabourin JC, Rufié P, Aparicio T, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer 1999 Dec;81(8):1351-5 Available from:
  3. 3.0 3.1 Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009 Oct 1;27(28):4656-63 Available from:
  4. Caplin M, Ruszniewski P, Pavel M, Ćwikła JB, Phan A, Raderer M, et al. A randomized double-blind placebo-controlled study of lanreotide antiproliferative response In patients with enteropancreatic neuroendocrine tumours (CLARINET). Eur J Cancer 2013 [cited 2014 Jun 12];49(3):Abstract E17-7103.
  5. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992 Feb 20;326(8):519-23 Available from:
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  8. Delaunoit T, Ducreux M, Boige V, Dromain C, Sabourin JC, Duvillard P, et al. The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option? Eur J Cancer 2004 Mar;40(4):515-20 Available from:
  9. Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 2004 Dec 1;22(23):4762-71 Available from:
  10. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 1979;2(4):327-34 Available from:
  11. Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 1984 Nov;2(11):1255-9 Available from:
  12. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG, Eastern Cooperative Oncology Group. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 2005 Aug 1;23(22):4897-904 Available from:
  13. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol 2001 Aug;12(8):1139-43 Available from:
  14. Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007 May 15;13(10):2986-91 Available from:
  15. Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006 Jan 20;24(3):401-6 Available from:
  16. Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 2009 Jan 1;15(1):338-45 Available from:
  17. Isacoff WH, Moss RA, Pecora AL, Fine RL. Temozolomide/capecitabine therapy for metastatic neuroendocrine tumours of the pancreas. A retrospective review. J Clin Oncol 2006 [cited 2014 Jun 12];24(18S): Abstract 14023 Available from:
  18. Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011 Jan 15;117(2):268-75 Available from:
  19. Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 2008 Mar 10;26(8):1316-23 Available from:
  20. Kulke MH, Stuart K, Earle CC, Bhargava P, Clark JW, Enzinger PC, et. al. A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol 2006 [cited 2014 Jun 12];24(18S): Abstract 4044 Available from:
  21. Venook AP, Ko AH, Tempero MA, Uy J, Weber T, Korn M, et. al. Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. J Clin Oncol 2008 [cited 2014 Jun 12];26(15S)(May 20 Supplement) Available from:
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  23. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011 Feb 10;364(6):501-13 Available from:
  24. Raymond E, Niccoli P, Raoul J, Bang Y, Borbath I, Lombard-Bohas C, et al.. Updated overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) of sunitinib (SU) versus placebo (PBO) for patients (Pts) with advanced unresectable pancreatic neuroendocrine tumors (NET). J Clin Oncol 2011 [cited 2014 Jun 12];29 (suppl): abstr 4008. Available from:
  25. Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006 Nov 6;95(9):1148-54 Available from:
  26. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008 Sep 10;26(26):4311-8 Available from:
  27. Yao JC, Lombard-Bohas C, Baudin E, et al. A phase II trial of daily oral RAD001 (everolimus) in patients with metastatic pancreatic neuroendocrine tumours (NET) after failure of cytotoxic chemotherapy. Proceedings ASCO GI; 2009 [cited 2014 Jun 12]. Report No.: Abstract 122. Available from:
  28. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011 Feb 10;364(6):514-23 Available from:
  29. RADIANT-2 Study Group, Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011 Dec 10;378(9808):2005-12 Available from:

Further Reading

  • Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group J Clin Oncol 2003 Jul 15;21(14):2689-96 [Abstract available at].
  • Pavel M, Hainsworth JD, Baudin E, Peeters M, Hoersch D, Anthony L, et. al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). Ann Oncol 2010 [cited 2014 Jun 12];21(Suppl 8) pg viii4 LBA8.

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